Wnt signaling plays a critical role in cell fate determination and tissue development (Nusse, R. and Varmus, H. E. (1992) Cell 69, 1073-1087; Cadigan, K. M., and Nusse, R. (1997) Genes Dev 11, 3286-3305). Certain members of this family of secreted glycoproteins interact with co-receptors, frizzled and LRP5/6, leading to inhibition of β-catenin phosphorylation by the serine threonine kinase, glycogen synthase kinase-β(GSK-3β) within a large cytoplasmic complex including Dishevelled (Dsh), APC and Axin (Giles, R. H., van Es, J. H., and Clevers, H. (2003) Biochim Biophys Acta 1653, 1-24). Inhibition of β-catenin phosphorylation impairs its degradation by the ubiquitin/proteasome pathway, resulting in accumulation of the uncomplexed cytosolic molecule. Uncomplexed β-catenin then translocates to the nucleus where it interacts with TCF/LEF, and activates target genes (Giles, R. H., van Es, J. H., and Clevers, H. (2003) Biochim Biophys Acta 1653, 1-24). Accumulating evidence indicates that signaling through the Wnt canonical pathway regulates the differentiation of adult stem cells in the epithelium of the colon (van de Wetering, M., de Lau, W., and Clevers, H. (2002) Cell 109 Suppl, S13-19) and skin (Alonso, L., and Fuchs, E. (2003) Genes Dev 17, 1189-1200), as well as in muscle (Polesskaya, A., Seale, P., and Rudnicki, M. A. (2003) Cell 113, 841-852) and hematopoietic cells (Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., and Weissman, I. L. (2003) Nature 423, 409-414). Constitutively activated Wnt signaling has also been shown to be causally involved in cancer (Polakis, P. (2000) Genes Dev 14, 1837-1851).
Extra-cellular inhibitors that function to fine-tune the spatial and temporal patterns of Wnt activity and act at the cell surface to inhibit Wnt signaling through its receptors have recently been discovered (Kawano, Y., and Kypta, R. (2003) J Cell Sci 116, 2627-2634). One group of Wnt antagonists is the secreted Frizzled Related Proteins (FRPs), which share sequence similarity with the Frizzled receptor CRD (cysteine rich domain), but lack the transmembrane and intracellular domains (Leyns, L., Bouwmeester, T., Kim, S. H., Piccolo, S., and De Robertis, E. M. (1997) Cell 88, 747-756; Wang, S., Krinks, M., Lin, K., Luyten, F. P., and Moos, M., Jr. (1997) Cell 88, 757-766; Finch, P. W., He, X., Kelley, M. J., Uren, A., Schaudies, R. P., Popescu, N. C., Rudikoff, S., Aaronson, S. A., Varmus, H. E., and Rubin, J. S. (1997) Proc Natl Acad Sci USA 94, 6770-6775). Through its CRD, FRP exhibits the ability to bind Wnt, form dimers and heterodimerize with frizzled (Leyns, L., Bouwmeester, T., Kim, S. H., Piccolo, S., and De Robertis, E. M. (1997) Cell 88, 747-756; Wang, S., Krinks, M., Lin, K., Luyten, F. P., and Moos, M., Jr. (1997) Cell 88, 757-766; Rattner, A., Hsieh, J. C., Smallwood, P. M., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., and Nathans, J. (1997) Proc Natl Acad Sci USA 94, 2859-2863; Lin, K., Wang, S., Julius, M. A., Kitajewski, J., Moos, M., Jr., and Luyten, F. P. (1997) Proc Natl Acad Sci USA 94, 11196-11200; Bafico, A., Gazit, A., Pramila, T., Finch, P. W., Yaniv, A., and Aaronson, S. A. (1999) J Biol Chem 274, 16180-16187). Thus, FRP may act not only to sequester Wnts but also to inhibit Wnt signaling via formation of non-functional complexes with the frizzled receptor. Another Wnt antagonist is designated Dickkopf-1 (DKK1), which is the prototype of a family of secreted proteins structurally unrelated to Wnt or Frizzled (Glinka, A., Wu, W., Delius, H., Monaghan, A. P., Blumenstock, C., and Niehrs, C. (1998) Nature 391, 357-362; Fedi, P., Bafico, A., Nieto Soria, A., Burgess, W. H., Miki, T., Bottaro, D. P., Kraus, M. H., and Aaronson, S. A. (1999) J Biol Chem 274, 19465-19472). DKK1 binds the Wnt co-receptor LRP6 and causes its endocytosis through formation of a ternary complex with the transmembrane protein Kremen (Mao, B., Wu, W., Li, Y., Hoppe, D., Stannek, P., Glinka, A., and Niehrs, C. (2001) Nature 411, 321-325; Bafico, A., Liu, G., Yaniv, A., Gazit, A., and Aaronson, S. A. (2001) Nat Cell Biol 3, 683-686; Semenov, M. V., Tamai, K., Brott, B. K., Kuhl, M., Sokol, S., and He, X. (2001) Curr Biol 11, 951-961; Mao, B., Wu, W., Davidson, G., Marhold, J., Li, M., Mechler, B. M., Delius, H., Hoppe, D., Stannek, P., Walter, C., et al. (2002 Nature 417, 664-667).
Wnts were initially identified as a consequence of their transcriptional activation by mouse mammary tumor virus promoter insertion, which initiates mammary tumor formation (Nusse, R., and Varmus, H. E. (1992). Cell 69, 1073-1087). Later studies established that genetic alterations afflicting APC and β-catenin, leading to increased uncomplexed β-catenin levels, occur very commonly in human colon and other cancers (Polakis, P. (2000) Genes Dev 14, 1837-1851; Giles, R. H., van Es, J. H., and Clevers, H. (2003) Biochim Biophys Acta 1653, 1-24). Despite the initial discovery of a Wnt autocrine transforming mechanism in the mouse model more than two decades ago, evidence of this mechanism in human cancer is lacking.
There is a continuing need for the development of chemotherapeutic agents useful for treating or preventing cancer, or for use in combination with known cancer therapies. The present invention meets such needs, and further provides other related advantages.